Caffeine is a xanthine derivative naturally found in coffee, tea, and cacao beans, as well as in high amounts in caffeinated beverages such as coffee, cola, and energy drinks.^2,3 It is generally considered safe at daily habitual intakes below 400 mg, while toxic effects are estimated to occur with intakes higher than 1.2 g, and a dose of 10 to 14 g is thought to be fatal.^2,3 Additionally, consuming 3 to 5 standard cups of coffee per day has been associated with a reduced risk of cardiovascular and chronic diseases.³ Energy drinks may pose a greater risk of adverse effects than other caffeinated beverages due to high episodic consumption which prevents tolerance development, their popularity among adolescents, unclear or high caffeine content, potential interactions with other ingredients like ginseng, and their combination with alcohol or recreational drugs such as marijuana.^3,4 Caffeine competitively inhibits adenosine receptors and exerts sympathomimetic effects by stimulating catecholamine release from the adrenal medulla, leading to increased intracellular calcium in myocytes and vascular smooth muscle.² These mechanisms may produce positive inotropic, chronotropic, and bathmotropic effects on cardiomyocytes.⁴ Additionally, caffeine’s adenosine antagonism and catecholamine-induced vasoconstriction have been linked to CAS in some case reports, increasing vascular smooth muscle contraction and the risk of adverse cardiovascular events.^5–7 It is important to note that, to date, there is insufficient data to confirm a direct correlation between energy drink consumption and severe cardiovascular adverse effects, including VA and death.^8,9 However, such effects may occur in cases of excessive consumption of energy drinks, in at-risk individuals (like adolescents and genetically predisposed individuals), or when combined with alcohol and illicit/recreational drugs, though the underlying mechanisms remain unclear.⁴

Cannabis, or marijuana, is one of the most popular worldwide recreational drugs due to global regulatory changes that have increased cannabis availability and consumption for recreational and medical use.¹⁰ The physiological effects of cannabis are derived primarily from its two best studied cannabinoids: Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The endogenous endocannabinoid system, consisting of endogenous endocannabinoids and cannabinoid receptors 1 (CB1) and CB2, plays a crucial role in maintaining homeostasis, including regulation of mood, pain, memory, metabolism, and cardiovascular function.¹⁰ The effects of THC and CBD are mediated through these receptors: CB1 is expressed in the brain, peripheral tissues, heart, and vasculature, while CB2 is primarily found in immune cells and the vasculature.¹⁰ CB1 activation by THC induces acute haemodynamic effects via sympathetic nervous system activation, leading to increased heart rate, blood pressure, myocardial contractility, and vascular tone.¹¹ Furthermore, THC can induce endothelial dysfunction and platelet aggregation.^10,11 In contrast, CBD has been shown to reduce heart rate and blood pressure while promoting vasodilation.¹⁰ THC exerts complex and unpredictable effects on the vascular system, including coronary artery vasoconstriction and vasodilation, which may contribute to an increased risk of acute coronary syndrome and arrhythmias.¹¹ Epidemiological studies and case series have linked marijuana use to a wide range of adverse cardiovascular events as reviewed in the scientific statement from the America Heart Association on medical marijuana,¹⁰ including acute coronary syndromes, coronary thrombosis, CAS, coronary dissection, heart failure, cardiomyopathies, stroke, supraventricular arrhythmias, VA, and SCD.^10,11 A recent population-based cross-sectional study of 434 104 individuals found that the prevalence of daily and non-daily cannabis use was 4% and 7.1%, respectively. Cannabis use was associated with adverse cardiovascular outcomes, with heavier use (measured by frequency per month) correlating with a higher likelihood of adverse events.¹² A systematic review of case reports on acute myocardial infarction associated with cannabis use found that 37% of cases had normal coronary angiograms. In these cases, myocardial infarction was hypothesized to result from coronary vasospasm or reduced coronary flow.¹³

We propose that a synergistic interaction between caffeine and cannabis played a role in triggering CAS, leading to life-threatening cardiac arrest. Our patient presented with adrenal hyperplasia and adenoma, but gallium PET showed no typical features of pheochromocytoma. The mild elevation in urinary metanephrines may be attributed to chronic caffeine intake-310 mg daily-which is shown to stimulate catecholamine release from adrenal medulla.² During hospitalisation, abstinence from caffeinated drinks normalized urinary metanephrines levels. However, re-exposure to caffeine from a single cola could trigger chest pain, ST segment elevation in anterior and lateral leads, and a subsequent PEA. In fact, ICA revealed spontaneous vasospasm in the ostial and proximal LAD and the proximal circumflex artery.

According to the 2022 European Society of Cardiology (ESC) guidelines for the management of patients with VA and the prevention of SCD,¹⁴ in survivors of SCD, testing with ergonovine, acetylcholine, or hyperventilation may aid in diagnosing coronary vasospasm, while cardiac MR is recommended to exclude other potential causes of SCD. Coronary vasospasm testing was not performed during the initial ICA, as the clinical presentation initially suggested pheochromocytoma/paraganglioma, which was later ruled out following a negative gallium PET scan. Following the second episode of aborted SCD, emergency ICA revealed spontaneous dynamic vasospasm, which resolved following the administration of intracoronary nitroglycerine.

The 2024 ESC guidelines for the management of chronic coronary syndromes (CCS) emphasize a patient-centered approach to the medical treatment of CAS.¹⁵ The CCS guidelines give a Class I recommendation for the use of CCBs as first-line therapy for symptom control and prevention of ischaemia and potentially fatal complications. In severe CAS, the CCS guidelines¹⁵ note that high doses of non-DHP CCBs may be necessary to control symptoms. In some cases, a combination of non-DHP with DHP CCBs may be required.¹⁵ The CCS guidelines also provide a Class II recommendation for the use of nitrates to prevent recurrent episodes.¹⁵ Additionally, nicorandil is suggested as an alternative treatment, although its use is limited due to frequent side effects.¹⁵ As per CCS guidelines, given the severity of CAS, our patient was treated with a combination non-DHP and DHP CCBs and nitrates with clinical benefit, in order to prevent recurrent ischaemia and potentially fatal complications. While avoiding common CAS triggers and adhering to optimal medical therapy are typically sufficient to prevent life-threatening events, the severity of CAS in our patient warranted ICD implantation. According to the VA and SCD guidelines,¹⁴ ICD placement should be considered for survivors of sudden cardiac arrest with CASs (Class IIa recommendation). Notably, ventricular fibrillation was documented during the initial OHCA, and the dual-chamber ICD enabled precise titration of CCBs, effectively reducing the frequency of vasospastic angina episodes.